Septic Shock: Pharmacologic Agents for Hemodynamic Support. Nathan E Cope, PharmD PGY2 Critical Care Pharmacy Resident

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1 Septic Shock: Pharmacologic Agents for Hemodynamic Support Nathan E Cope, PharmD PGY2 Critical Care Pharmacy Resident

2 Objectives Define septic shock and briefly review pathophysiology Outline receptor selectivity and physiologic functions Examine guidelines and recommendations Compare vasopressors used in septic shock Distinguish which patients benefit from corticosteroids Summarize the when and why of vasopressors, inotropes, and steroids

3 Agents of Interest Norepinephrine Dopamine Epinephrine Vasopressin Phenylephrine Dobutamine Hydrocortisone

4 Septic Shock Definition Hypotension refractory to adequate fluid resuscitation Pathophysiology intravascular volume (capillary leakage) arteriole resistance venous capacitance cardiac contractility

5 Receptor Types & Physiological Function Vasoconstriction Heart Rate Splanchnic Blood Flow Other α β contractility V antidiuretic D renal blood flow Basic and Clinical Pharmacology 11 th ed

6 Spectrum of Activity α β Phenylephrine Epinephrine Dobutamine Norepinephrine

7 Relative Receptor Activity α β D Epinephrine Norepinephrine Phenylephrine Dobutamine +/ Dopamine Dose Dependent α β α >> β α >>>>> β β >>>>> α Adopted from: Tintinalli s Emergency Medicine Basic and Clinical Pharmacology 11 th ed.

8 Surviving Sepsis Guidelines Surviving Sepsis, CCM 2013

9 Grading of Recommendations 1 Strong 2 Weak A B C D High Moderate Low Very Low Surviving Sepsis, CCM 2013

10 Surviving Septic Shock: Vasopressors 1. Target a MAP of 65 mmhg (1C) Surviving Sepsis, CCM 2013

11 Vascular Beds

12 Evaluating Tissue Perfusion Mean Arterial Pressure (MAP) Blood Pressure Lactate SvO 2 Urinary Output Skin perfusion Mental status

13 Surviving Septic Shock: Vasopressors 2. Norepinephrine as first choice (1B) Surviving Sepsis, CCM 2013

14 Norepinephrine Preparation Initial Rate Adjustment Soft Max Units 4mg / 250ml D5W every 5 min 30 mcg / min α β D 0 α and β activity, but prominently α Vasoconstriction with opposing β Little change in heart rate Basic and Clinical Pharmacology 11 th ed

15 Dopamine Preparation Initial Rate Adjustment Max Rate Units PREMIX (800mg / 500ml D5W) every 3-5 min 20 mcg / kg / min Dose-Dependent Pharmacological Profile Low Intermediate High D β <5 mcg / kg / min 5-10 mcg / kg / min >10 mcg / kg/ min α D β + D α + β + D Basic and Clinical Pharmacology 11 th ed

16 Norepinephrine vs. Dopamine De Backer, et al Not specific to septic shock No difference in rate of death Greater adverse events with dopamine Vasu, et al Systemic Review, 6 RCT s Pooled analysis favored norepinephrine More adverse effects with dopamine Short term mortality favoring norepinephrine De Backer, et al Meta-analysis Dopamine increased mortality De Backer, et al. NEJM 2010 De Backer, et al. CCM 2012 Vasu, et al. Intensive Care Med 2012

17 Surviving Septic Shock: Vasopressors 3. Epinephrine can be substituted for or added to norepinephrine for adequate blood pressure (2B) Surviving Sepsis, CCM 2013

18 Epinephrine Preparation Initial Rate Adjustment Soft Max Units 4mg / 250ml NS every 3-5 min 20 mcg / min α +++ β +++ D 0 Hyperlactatemia May decrease splanchnic circulation No evidence of difference from norepinephrine Basic and Clinical Pharmacology 11 th ed

19 Surviving Septic Shock: Vasopressors 4. Vasopressin can be added to norepinephrine to raise MAP or decrease norepinephrine (Ungraded) 5. Not recommended as initial single agent, and higher doses only for salvage therapy (Ungraded) Surviving Sepsis, CCM 2013

20 Vasopressin Preparation Initial Rate Adjustment Max Rate Units 40 units / 250ml NS 0.03 rare 0.04 units / min Relative vasopressin deficiency Norepinephrine dose sparing effect VASST trial no difference in outcome <15 mcg/min of NE, better survival More digital ischemia with vasopressin V Vasoconstriction Russell, et al. NEJM 2008 Basic and Clinical Pharmacology 11 th ed

21 Surviving Septic Shock: Vasopressors 6. Dopamine as an alternative in select patients (2C) Surviving Sepsis, CCM 2013

22 Dopamine Preparation Initial Rate Adjustment Max Rate Units PREMIX (800mg / 500ml D5W) every 3-5 min 20 mcg / kg / min Selected Patients Low risk of tachyarrhythmia s Absolute or relative bradycardia Balance with risk of adverse arrhythmias Surviving Sepsis, CCM 2013 Basic and Clinical Pharmacology 11 th ed

23 Surviving Septic Shock: Vasopressors 7. Phenylephrine not recommended with few exceptions (1C) Surviving Sepsis, CCM 2013

24 Phenylephrine Preparation Initial Rate Adjustment Soft Max Units 50mg / 250ml NS every 5 min 300 mcg / min α β D 0 Exceptions for use 1. Norepinephrine serious arrhythmias 2. Cardiac output is known to be high 3. Added for salvage therapy Caution Can decrease stroke volume, cause bradycardia Surviving Sepsis, CCM 2013 Basic and Clinical Pharmacology 11 th ed

25 Surviving Septic Shock: Vasopressors 8. Do not use low-dose dopamine for renal protection (1A) Surviving Sepsis, CCM 2013

26 Low Dose Dopamine <5 mcg/kg/min May increase renal blood flow and UOP No difference in outcomes, may induce harm Bellomo, et al (RCT) No difference in peak serum creatinine Does not confer renal protection Kellum, et al (meta-analysis) 58 studies Did not prevent mortality, onset of AKI, or dialysis Bellomo, et al Kellum, et al. 2001

27 Surviving Septic Shock: Inotropic Therapy 1. Dobutamine in addition to vasopressor for myocardial dysfunction or ongoing hypoperfusion despite volume and MAP (1C) 2. Do not push supranormal, predetermined cardiac index (1B) Surviving Sepsis, CCM 2013

28 Dobutamine Preparation Initial Rate Adjustment Max Rate Units PREMIX (500mg / 250ml NS) q5-10 min 20 mcg / kg / min α β +/ D 0 Mixed α stimulation/blockade Systemic vasodilation Myocardial contractility Minimal heart rate changes Basic and Clinical Pharmacology 11 th ed

29 Surviving Septic Shock: Corticosteroids 1. Only add hydrocortisone if refractory to fluids and vasopressors (2C) 2. Suggest against use of ACTH stimulation test (2B) Surviving Sepsis, CCM 2013

30 Surviving Septic Shock: Corticosteroids 3. Taper off when vasopressors no longer required (2D) 4. Not for treatment of sepsis without shock (1D) 5. Continuous infusion over bolus (2D) Surviving Sepsis, CCM 2013

31 Steroid Activity Glucocorticoid Mineralocorticoid Steroid Equivalent Dose Anti-inflammatory Mineralocorticoid Hydrocortisone 20 mg 1 1 Prednisone 5 mg Methylprednisolone 4 mg Dexamethosone 0.8 mg 25 0 Fludrocortisone Basic and Clinical Pharmacology 11 th ed

32 Corticosteroids Annane, et al French multicenter RCT (specific to refractory septic shock) Significant shock reversal and reduction in mortality No significant difference in responders vs non-responders CORTICUS trial, Enrolled patients without sustained shock, lower risk of death Decrease time to shock resolution, but no mortality benefit Patient that persisted <90 SBP at 1 day, despite fluids and vasopressors 11.2% absolute reduction in mortality in steroid group Annane, et al. JAMA 2002 Sprung, et al. NEJM 2008

33 Continuous versus Bolus Hydrocortisone 200 mg/day 200 mg / 24h continuous infusion or 50 mg every 6h Concerns for peak effect with bolus Hyperglycemia, hypernatremia Weber-Carstens, et al Reality Glucose peak levels ~150 mg/dl in study No significant individual variability found No association with patient outcomes Continuous infusion not current clinical practice Weber-Carstens, et al. Intensive Care Med 2006

34 Weber-Carstens Study Weber-Carstens, et al. Intensive Care Med 2006

35 Summary Vasopressors when refractory to adequate fluids Receptor activity plays a major role in agent selection, with norepinephrine being the first line for a vast majority of patients Vasopressin added upon escalation of norepinephrine may spare dosing, offer less side effects, and add possible survival benefit Dopamine, Dobutamine, and Phenylephrine are appropriate for only select patients or salvage therapy Corticosteroids when refractory to fluids and vasopressors

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